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Abstract: TH-PO623

Arginine Bioavailability Correlates with Cardiac Remodeling in Mice with CKD

Session Information

Category: Health Maintenance, Nutrition, and Metabolism

  • 1301 Health Maintenance, Nutrition, and Metabolism: Basic

Authors

  • Reyes, Loretta, Emory University School of Medicine, Atlanta, Georgia, United States
  • Kelleman, Mike, Emory University School of Medicine, Atlanta, Georgia, United States
  • Harris, Frank, Emory University School of Medicine, Atlanta, Georgia, United States
  • Brown, Lou ann S., Emory University School of Medicine, Atlanta, Georgia, United States
  • Morris, Claudia R., Emory University School of Medicine, Atlanta, Georgia, United States
  • Winterberg, Pamela D., Emory University School of Medicine, Atlanta, Georgia, United States
Background

Nitric oxide (NO) is critical for vascular homeostasis. Arginine (Arg), the sole nitrogen donor for NO synthesis, is the common substrate for NO synthase & arginase enzymes (Fig 1). Global arginine bioavailability ratio (GABR) has been proposed to reflect substrate availability for NO synthesis by accounting for Arg concentration relative to its catabolic products ornithine (Orn) & citrulline (Cit). Low GABR has been associated with increased mortality in adults with heart failure & coronary artery disease. This study aimed to determine the relationship between GABR & measures of cardiac structure & function in mice with CKD.

Methods

CKD was established in male 129X1/SvJ mice via 2-stage partial nephrectomy. Plasma was collected at 8 & 16 wks post surgery & Arg, Orn & Cit were measured by LC/MS/MS. GABR was calculated as [Arg]/([Orn]+[Cit]). Echos were performed at 8 & 16 wks. Relative wall thickness (RWT) was calculated using M-mode parasternal long-axis measurements (IVS;d+LVPW;d)/LVID;d & myocardial performance index (MPI) as (IVCT+IVRT/ET) on trans-mitral Doppler. In a separate experiment, CKD mice received diet supplemented with Arg or alanine (nitrogen control) for 12 wks to determine effect on myocardial function.

Results

GABR was significantly reduced in mice with CKD compared to controls at both 8 wks [median (IQR) 0.56 (0.52-0.61) vs 0.74 (0.72-0.78); p=0.01] & 16 wks [0.41 (0.36-0.49) vs 0.64 (0.55-0.68); p=0.03]. There was a significant association between GABR & LVH (RWT; r=-0.39, p=0.02) & diastolic dysfunction (E/A ratio; r=0.37, p=0.04). At 12 wks, CKD mice on Arg supplementation compared to mice on control diet showed improved LVH (RWT 0.47±0.08 vs 0.58±0.06; p=0.01) & MPI (0.81±0.12 vs 1.05±0.11; p<0.01).

Conclusion

GABR is decreased in mice with CKD & correlates with worsening structural (RWT) & functional (E/A ratio) cardiac changes. Interestingly, Arg supplementation improved LVH & MPI at 12 wks. Additional studies are underway to determine underlying etiology of reduced GABR in CKD.

Funding

  • NIDDK Support